Human neoplasia is commonly associated with systemic manifestations resembling those seen in classical endocrine disorders in which there is overproduction of hormones. Humor hypercalcemia of malignancy (HHM), is one of the most common examples of this phenomenon. Circulating tumor-derived factors are understood to cause hypercalcemia by acting peripherally on bone, kidney and perhaps intestine but the nature of such factors has, until recently, been controversial. During the last three years the structure of a human parathyroid hormone-related protein (PTHrP) has been determined. The peptide shares sufficient N-terminal homology with PTH to interact with classical PTH receptors but the complete protein is the product of a different gene. Moreover, PTHrP is produced in normal tissues where it may act as a growth or differentiation factor. Although our initial studies showed that a synthetic 1-34 fragment of PTHrP mimicked some of the classical actions of PTH, emerging evidence suggests several important differences in the biological profiles for these two related proteins. This project will attempt to identify differences which might explain why certain clinical features of patients with HHM are opposite to those seen in primary hyperparathyroidism. We will employ a multiparameter rat bioassay to establish the relative importance of bone, kidney and intestinal calcium transport in the production of hypercalcemia in vivo. The physiological changes produced by exogenous PTHrP infusion will then be compared to those observed in two animal models of HHM in which hypercalcemia is produced in rodents by inoculation with a PTHrP-producing tumors. On a separate level of inquiry we will evaluate the ability of PTH receptor antagonists to block PTHrP activity achieved in the PTHrP infused animals and in the hypercalcemic tumor-bearing animals. A final aspect of the project will examine the molecular mechanisms by which lymphocyte transformation by HTLV-1 is coupled to aberrant expression of PTHrP. Collectively, these studies will provide critical information on the pathogenesis of HHM and will promote insight into PTH structure-activity relationships which could eventually lead to the design of antagonists for treatment of the disease.